Use of substituted 2, 3-dihydroimidazo[1,2-c]quinazolines for the treatment of myeloma

ABSTRACT

The present invention relates to the use of 2,3-dihydroimidazo[1,2-c]quinazoline compounds, and of pharmaceutical compositions containing such compounds, for the treatment or prophylaxis of multiple myeloma, as a sole agent or in combination with other one or more other active ingredients.

The present invention relates to the use of2,3-dihydroimidazo[1,2-c]quinazoline compounds, and of pharmaceuticalcompositions containing such compounds, for the treatment or prophylaxisof multiple myeloma, which is also known as myeloma, plasma cellmyeloma, or as Kahler's disease (after Otto Kahler), and which is a typeof cancer of plasma cells in bone marrow that produce antibodies, as asole agent or in combination with one or more other active ingredients.

BACKGROUND OF THE INVENTION

In the last decade the concept of developing anti-cancer medicationswhich target abnormally active protein kinases has led to a number ofsuccesses. In addition to the actions of protein kinases, lipid kinasesalso play an important role in generating critical regulatory secondmessengers. The PI3K family of lipid kinases generates3′-phosphoinositides that bind to and activate a variety of cellulartargets, initiating a wide range of signal transduction cascades(Vanhaesebroeck et al., 2001; Toker, 2002; Pendaries et al., 2003;Downes et al., 2005). These cascades ultimately induce changes inmultiple cellular processes, including cell proliferation, cellsurvival, differentiation, vesicle trafficking, migration, andchemotaxis.

PI3Ks can be divided into three distinct classes based upon differencesin both structure, and substrate preference. While members of the ClassII family of PI3Ks have been implicated in the regulation of tumorgrowth (Brown and Shepard, 2001; Traer et al., 2006), the bulk ofresearch has focused on the Class I enzymes and their role in cancer(Vivanco And Sawyers, 2002; Workman, 2004, Chen et al., 2005; Hennesseyet al., 2005; Stauffer et al., 2005; Stephens et al., 2005; Cully etal., 2006). Class I PI3Ks have traditionally been divided into twodistinct sub-classes based upon differences in protein subunitcomposition. The Class I_(A) PI3Ks are comprised of a catalytic p110catalytic subunit (p110α, β or γ) heterodimerized with a member of thep85 regulatory subunit family. In contrast, the Class I_(B) PI3Kcatalytic subunit (p110γ) heterodimerizes with a distinct p101regulatory subunit (reviewed by Vanhaesebroeck and Waterfield, 1999;Funaki et al., 2000; Katso et al., 2001). The C-terminal region of theseproteins contains a catalytic domain that possesses distant homology toprotein kinases. The PI3Kγ structure is similar to Class I_(A) p110s,but lacks the N-terminal p85 binding site (Domin and Waterfield, 1997).Though similar in overall structure, the homology between catalytic p110subunits is low to moderate. The highest homology between the PI3Kisoforms is in the kinase pocket of the kinase domain.

The Class I PI3K isoforms associate with activated receptor tyrosinekinases (RTKs) (including PDGFR, EGFR, VEGFR, IGF1-R, c-KIT, CSF-R andMet), cytokine receptors, GPCRs, integrins, or with tyrosinephosphorylated adapter proteins (such as Grb2, Cbl, IRS-1 or Gab1), viatheir p85 regulatory subunits resulting in stimulation of the lipidkinase activity. Activation of the lipid kinase activity of the p110βand p110γ isoforms has been shown to occur in response to binding toactivated forms of the ras Oncogene (Kodaki et al, 1994). In fact, theoncogenic activity of these isoforms may require binding to ras (Kang etal., 2006). In contrast, the p110α and p110δ isoforms exhibit oncogenicactivity independent of ras binding, through constitutive activation ofAkt.

Class I PI3Ks catalyze the conversion of PI(4,5)P₂ [PIP₂] to PI(3,4,5)P₃[PIP₃]. The production of PIP₃ by PI3K affects multiple signalingprocesses that regulate and coordinate the biological end points of cellproliferation, cell survival, differentiation and cell migration. PIP₃is bound by Pleckstrin-Homology (PH) domain-containing proteins,including the phosphoinositide-dependent kinase, PDK1 and the Aktproto-oncogene product, localizing these proteins in regions of activesignal transduction and also contributing directly to their activation(Klippel et al., 1997; Fleming et al., 2000; Itoh and Takenawa, 2002;Lemmon, 2003). This co-localization of PDK1 with Akt facilitates thephosphorylation and activation of Akt. Carboxy-terminal phosphorylationof Akt on Ser⁴⁷³ promotes phosphorylation of Thr³⁰⁸ in the Aktactivation loop (Chan and Tsichlis, 2001; Hodgekinson et al., 2002;Scheid et al., 2002; Hresko et al., 2003). Once active, Aktphosphorylates and regulates multiple regulatory kinases of pathwaysthat directly influence cell cycle progression and cell survival.

Many of the effects of Akt activation are mediated via its negativeregulation of pathways which impact cell survival and which are commonlydysregulated in cancer. Akt promotes tumor cell survival by regulatingcomponents of the apoptotic and cell cycle machinery. Akt is one ofseveral kinases that phosphorylate and inactivate pro-apoptotic BADproteins (del Paso et al., 1997; Pastorino et al., 1999). Akt may alsopromote cell survival through blocking cytochrome C-dependent caspaseactivation by phosphorylating Caspase 9 on Ser¹⁹⁶ (Cardone et al.,1998).

Akt impacts gene transcription on several levels. The Akt-mediatedphosphorylation of the MDM2 E3 ubiquitin ligase on Ser¹⁶⁶ and Ser¹⁸⁶facilitates the nuclear import of MDM2 and the formation and activationof the ubiquitin ligase complex. Nuclear MDM2 targets the p53 tumorsuppressor for degradation, a process that can be blocked by LY294002(Yap et al., 2000; Ogarawa et al., 2002). Downregulation of p53 by MDM2negatively impacts the transcription of p53-regulated pro-apoptoticgenes (e.g. Bax, Fas, PUMA and DR5), the cell cycle inhibitor,p21^(CiP1), and the PTEN tumor suppressor (Momand et al., 2000; Hupp etal., 2000; Mayo et al., 2002; Su et al., 2003). Similarly, theAkt-mediated phosphorylation of the Forkhead transcription factors FKHR,FKHRL and AFX (Kops et al., 1999; Tang et al., 1999), facilitates theirbinding to 14-3-3 proteins and export from the cell nucleus to thecytosol (Brunet et al., 1999). This functional inactivation of Forkheadactivity also impacts pro-apoptotic and pro-angiogenic genetranscription including the transcription of Fas ligand (Ciechomska etal., 2003) Bim, a pro-apoptotic Bcl-2 family member (Dijkers et al.,2000), and the Angiopoietin-1 (Ang-1) antagonist, Ang-2 (Daly et al.,2004). Forkhead transcription factors regulate the expression of thecyclin-dependent kinase (Cdk) inhibitor p27^(KiP1). Indeed, PI3Kinhibitors have been demonstrated to induce p27^(KiP1) expressionresulting in Cdk1 inhibition, cell cycle arrest and apoptosis (Dijkerset al., 2000). Akt is also reported to phosphorylate p21^(CiP1) onThr¹⁴⁵ and p27^(KiP1) on Thr¹⁵⁷ facilitating their association with14-3-3 proteins, resulting in nuclear export and cytoplasmic retention,preventing their inhibition of nuclear Cdks (Zhou et al., 2001; Motti etal., 2004; Sekimoto et al., 2004). In addition to these effects, Aktphosphorylates IKK (Romashkova and Makarov, 1999), leading to thephosphorylation and degradation of IκB and subsequent nucleartranslocation of NFκB, resulting in the expression of survival genessuch as IAP and Bcl-X_(L).

The PI3K/Akt pathway is also linked to the suppression of apoptosisthrough the JNK and p38^(MAPK) MAP Kinases that are associated with theinduction of apoptosis. Akt is postulated to suppress JNK and p38^(MAPK)signaling through the phosphorylation and inhibition of two JNK/p38regulatory kinases, Apoptosis Signal-regulating Kinase 1 (ASK1) (Kim etal., 2001: Liao and Hung, 2003; Yuan et al., 2003), and Mixed LineageKinase 3 (MLK3) (Lopez-Ilasaca et al., 1997; Barthwal et al., 2003;Figueroa et al., 2003;). The induction of p38^(MAPK) activity isobserved in tumors treated with cytotoxic agents and is required forthose agents to induce cell death (reviewed by Olson and Hallahan,2004). Thus, inhibitors of the PI3K pathway may promote the activitiesof co-administered cytotoxic drugs.

An additional role for PI3K/Akt signaling involves the regulation ofcell cycle progression through modulation of Glycogen Synthase Kinase 3(GSK3) activity. GSK3 activity is elevated in quiescent cells, where itphosphorylates cyclin D₁ on Ser²⁸⁶, targeting the protein forubiquitination and degradation (Diehl et al., 1998) and blocking entryinto S-phase. Akt inhibits GSK3 activity through phosphorylation on Ser⁹(Cross et al., 1995). This results in the elevation of Cyclin D₁ levelswhich promotes cell cycle progression. Inhibition of GSK3 activity alsoimpacts cell proliferation through activation of the wnt/beta-cateninsignaling pathway (Abbosh and Nephew, 2005; Naito et al., 2005; Wilkeret al., 2005; Kim et al., 2006; Segrelles et al., 2006). Akt mediatedphosphorylation of GSK3 results in stabilization and nuclearlocalization of the beta-catenin protein, which in turn leads toincreased expression of c-myc and cyclin D1, targets of thebeta-catenin/Tcf pathway.

Although PI3K signaling is utilized by many of the signal transductionnetworks associated with both oncogenes and tumor suppressors, PI3K andits activity have been linked directly to cancer. Overexpression of boththe p110α and p110β isoforms has been observed in bladder and colontumors and cell lines, and overexpression generally correlates withincreased PI3K activity (Bénistant et al., 2000). Overexpression ofp110α has also been reported in ovarian and cervical tumors and tumorcell lines, as well as in squamous cell lung carcinomas. Theoverexpression of p110α in cervical and ovarian tumor lines isassociated with increased PI3K activity (Shayesteh et al., 1999; Ma etal., 2000). Elevated PI3K activity has been observed in colorectalcarcinomas (Phillips et al., 1998) and increased expression has beenobserved in breast carcinomas (Gershtein et al., 1999).

Over the last few years, somatic mutations in the gene encoding p110α(PIK3CA) have been identified in numerous cancers. The data collected todate suggests that PIK3CA is mutated in approximately 32% of colorectalcancers (Samuels et al., 2004; Ikenoue et al., 2005), 18-40% of breastcancers (Bachman et al., 2004; Campbell et al., 2004; Levine et al.,2005; Saal et al., 2005; Wu et al., 2005), 27% of glioblastomas (Samuelset al., 2004; Hartmann et al., 2005, Gallia et al., 2006), 25% ofgastric cancers (Byun et al., 2003; Samuels et al., 2004; Li et al.,2005), 36% of hepatocellular carcinomas (Lee et al., 2005), 4-12% ofovarian cancers (Levine et al., 2005; Wang et al., 2005), 4% of lungcancers (Samuels et al., 2004; Whyte and Holbeck, 2006), and up to 40%of endometrial cancers (Oda et al., 2005). PIK3CA mutations have beenreported in oligodendroma, astrocytoma, medulloblastoma, and thyroidtumors as well (Broderick et al., 2004; Garcia-Rostan et al., 2005).Based upon the observed high frequency of mutation, PIK3CA is one of thetwo most frequently mutated genes associated with cancer, the otherbeing K-ras. More than 80% of the PIK3CA mutations cluster within tworegions of the protein, the helical (E545K) and catalytic (H1047R)domains. Biochemical analysis and protein expression studies havedemonstrated that both mutations lead to increased constitutive p110□catalytic activity and are in fact, oncogenic (Bader et al., 2006; Kanget al., 2005; Samuels et al., 2005; Samuels and Ericson, 2006).Recently, it has been reported that PIK3CA knockout mouse embryofibroblasts are deficient in signaling downstream from various growthfactor receptors (IGF-1, Insulin, PDGF, EGF), and are resistant totransformation by a variety of oncogenic RTKs (IGFR, wild-type EGFR andsomatic activating mutants of EGFR, Her2/Neu) (Zhao et al., 2006).

Functional studies of PI3K in vivo have demonstrated that siRNA-mediateddownregulation of p110β inhibits both Akt phosphorylation and HeLa celltumor growth in nude mice (Czauderna et al., 2003). In similarexperiments, siRNA-mediated downregulation of p110β was also shown toinhibit the growth of malignant glioma cells in vitro and in vivo (Pu etal., 2006). Inhibition of PI3K function by dominant-negative p85regulatory subunits can block mitogenesis and cell transformation (Huanget al., 1996; Rahimi et al., 1996). Several somatic mutations in thegenes encoding the p85α and p85β regulatory subunits of PI3K that resultin elevated lipid kinase activity have been identified in a number ofcancer cells as well (Janssen et al., 1998; Jimenez et al., 1998; Philpet al., 2001; Jucker et al., 2002; Shekar et al., 2005). NeutralizingPI3K antibodies also block mitogenesis and can induce apoptosis in vitro(Roche et al., 1994: Roche et al., 1998; Bénistant et al., 2000). Invivo proof-of-principle studies using the PI3K inhibitors LY294002 andwortmannin, demonstrate that inhibition of PI3K signaling slows tumorgrowth in vivo (Powis et al., 1994; Shultz et al., 1995; Semba et al.,2002; Ihle et al., 2004).

Overexpression of Class I PI3K activity, or stimulation of their lipidkinase activities, is associated with resistance to both targeted (suchas imatinib and tratsuzumab) and cytotoxic chemotherapeutic approaches,as well as radiation therapy (West et al., 2002; Gupta et al., 2003;Osaki et al., 2004; Nagata et al., 2004; Gottschalk et al., 2005; Kim etal., 2005). Activation of PI3K has also been shown to lead to expressionof multidrug resistant protein-1 (MRP-1) in prostate cancer cells andthe subsequent induction of resistance to chemotherapy (Lee et al.,2004).

The importance of PI3K signaling in tumorigenesis is further underscoredby the findings that the PTEN tumor suppressor, a PI(3)P phosphatase, isamong the most commonly inactivated genes in human cancers (Li et al.,1997, Steck et al., 1997; Ali et al., 1999; Ishii et al., 1999). PTENdephosphorylates PI(3,4,5)P₃ to PI(4,5)P₂ thereby antagonizingPI3K-dependent signaling. Cells containing functionally inactive PTENhave elevated levels of PIP₃, high levels of activity of PI3K signaling(Haas-Kogan et al., 1998; Myers et al., 1998; Taylor et al., 2000),increased proliferative potential, and decreased sensitivity topro-apoptotic stimuli (Stambolic et al., 1998). Reconstitution of afunctional PTEN suppresses PI3K signaling (Taylor et al., 2000),inhibits cell growth and re-sensitizes cells to pro-apoptotic stimuli(Myers et al., 1998; Zhao et al., 2004). Similarly, restoration of PTENfunction in tumors lacking functional PTEN inhibits tumor growth in vivo(Stahl et al., 2003; Su et al., 2003; Tanaka and Grossman, 2003) andsensitizes cells to cytotoxic agents (Tanaka and Grossman, 2003).

The class I family of PI3Ks clearly plays an important role in theregulation of multiple signal transduction pathways that promote cellsurvival and cell proliferation, and activation of their lipid kinaseactivity contributes significantly to the development of humanmalignancies. Furthermore, inhibition of PI3K may potentially circumventthe cellular mechanisms that underlie resistance to chemotherapeuticagents. A potent inhibitor of Class I PI3K activities would thereforehave the potential not only to inhibit tumor growth but to alsosensitize tumor cells to pro-apoptotic stimuli in vivo.

Signal transduction pathways originating from chemoattractant receptorsare considered to be important targets in controlling leukocyte motilityin inflammatory diseases. Leukocyte trafficking is controlled bychemoattractant factors that activate heterotrimeric GPCRs and therebytrigger a variety of downstream intracellular events. Signaltransduction along one of these pathways that results in mobilization offree Ca²⁺, cytoskelatal reorganization, and directional movement dependson lipid-derived second messengers producted by PI3K activity (Wymann etal., 2000; Stein and Waterfield, 2000).

PI3Kγ modulates baseline cAMP levels and controls contractility incells. Recent research indicates that alterations in baseline cAMPlevels contribute to the increased contractility in mutant mice. Thisresearch, therefore, shows that PI3Kγ inhibitors would afford potentialtreatments for congestive heart failure, ischemia, pulmonaryhypertension, renal failure, cardiac hypertrophy, atherosclerosis,thromboembolism, and diabetes.

PI3K inhibitors would be expected to block signal transduction fromGPCRs and block the activation of various immune cells, leading to abroad anti-inflammatory profile with potential for the treatment ofinflammatory and immunoregulatory diseases, including asthma, atopicdermatitis, rhinitis, allergic diseases, chronic obstructive pulmonarydisease (COPD), septic shock, joint diseases, autoimmune pathologiessuch as rheumatoid arthritis and Graves' disease, diabetes, cancer,myocardial contractility disorders, thromboembolism, andatherosclerosis.

Multiple myeloma is the second most common haematologic malignancy, with20,000 new cases per year (Jemal A, et al, Cancer J. Clin., 2007, 57:43-66), and remains incurable with a median survival of 3 to 5 years(Kyle R A, Rajkumar S V. Multiple myeloma. N. Engl. J. Med., 2004, 351:1860-73).

Further, as multiple myeloma is a plasma cell malignancy characterisedby complex heterogeneous cytogenetic abnormalities, the bone marrowmicroenvironment promotes multiple myeloma cell growth and resistance toconventional therapies.

The present invention is thus to provide compounds for the preparationof a medicament for use in the treatment of multiple myeloma.

To the Applicant's knowledge, no generic or specific disclosure orsuggestion in the prior art is known that2,3-dihydroimidazo[1,2-c]quinazoline compounds would be effective in thetreatment or prophylaxis of multiple myeloma.

It has been found, and this is the basis of the present invention, that2,3-dihydroimidazo[1,2-c]quinazoline compounds, as described and definedherein, show a beneficial effect in the treatment of multiple myeloma.

Accordingly, the present invention relates to the use of2,3-dihydroimidazo[1,2-c]quinazoline compounds and of pharmaceuticalcompositions containing such compounds, for the preparation of amedicament for the treatment or prophylaxis of multiple myeloma, whichis also known as myeloma, plasma cell myeloma, or as Kahler's disease(after Otto Kahler), and which is a type of cancer of plasma cells inbone marrow that produce antibodies, as a sole agent or in combinationwith other one or more other active ingredients.

DESCRIPTION OF THE INVENTION

A first embodiment of the present invention relates to the use of acompound of general formula (A):

in which:

X represents CR⁵R⁶ or NH;

Y¹ represents CR³ or N;

the chemical bond between Y²

Y³ represents a single bond or double bond, with the proviso that whenthe Y²

Y³ represents a double bond, Y² and Y³ independently represent CR⁴ or N,and

when Y²

Y³ represents a single bond, Y² and Y³ independently represent CR³R⁴ orNR⁴;

Z¹, Z², Z³ and Z⁴ independently represent CH, CR² or N;

-   -   R¹ represents aryl optionally having 1 to 3 substituents        selected from R¹¹, C₃₋₈ cycloalkyl optionally having 1 to 3        substituents selected from R¹¹,        -   C₁₋₆ alkyl optionally substituted by aryl, heteroaryl, C₁₋₆            alkoxyaryl, aryloxy, heteroaryloxy or one or more halogen,        -   C₁₋₆ alkoxy optionally substituted by carboxy, aryl,            heteroaryl, C₁₋₆ alkoxyaryl, aryloxy, heteroaryloxy or one            or more halogen, or        -   a 3 to 15 membered mono- or bi-cyclic heterocyclic ring that            is saturated or unsaturated, optionally having 1 to 3            substituents selected from R¹¹, and contains 1 to 3            heteroatoms selected from the group consisting of N, O and            S,        -   wherein        -   R¹¹ represents halogen, nitro, hydroxy, cyano, carboxy,            amino, N—(C₁₋₆alkyl)amino, N-(hydroxyC₁₋₆alkyl)amino,            N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆acyl)amino,            N-(formyl)-N—(C₁₋₆alkyl)amino, N—(C₁₋₆alkanesulfonyl)amino,            N-(carboxyC₁₋₆alkyl)-N—(C₁₋₆alkyl)amino,            N—(C₁₋₆alkoxycabonyl)amino, N—[N,N-di(C₁₋₆alkyl)amino            methylene]amino, N—[N,N-di(C₁₋₆alkyl)amino            (C₁₋₆alkyl)methylene]amino, N—[N,N-di(C₁₋₆alkyl)amino            C₂₋₆alkenyl]amino, aminocarbonyl,            N—(C₁₋₆alkyl)aminocarbonyl, N,N-di(C₁₋₆alkyl)aminocarbonyl,            C₃₋₈cycloalkyl, C₁₋₆ alkylthio, C₁₋₆alkanesulfonyl,            sulfamoyl, C₁₋₆alkoxycarbonyl,        -   N-arylamino wherein said aryl moiety is optionally having 1            to 3 substituents selected from R¹⁰¹, N-(aryl            C₁₋₆alkyl)amino wherein said aryl moiety is optionally            having 1 to 3 substituents selected from R¹⁰¹, aryl            C₁₋₆alkoxycarbonyl wherein said aryl moiety is optionally            having 1 to 3 substituents selected from R¹⁰¹,        -   C₁₋₆alkyl optionally substituted by mono-, di- or            tri-halogen, amino, N—(C₁₋₆alkyl)amino or            N,N-di(C₁₋₆alkyl)amino,        -   C₁₋₆alkoxy optionally substituted by mono-, di- or            tri-halogen, N—(C₁₋₆alkyl)sulfonamide, or            N-(aryl)sulfonamide,        -   or        -   a 5 to 7 membered saturated or unsaturated ring having 1 to            3 heteroatoms selected from the group consisting of O, S and            N, and optionally having 1 to 3 substituents selected from            R¹⁰¹        -   wherein        -   R¹⁰¹ represents halogen, carboxy, amino, N—(C₁₋₆            alkyl)amino, N,N-di(C₁₋₆alkyl)amino, aminocarbonyl,            N—(C₁₋₆alkyl)amino-carbonyl, N,N-di(C₁₋₆alkyl)aminocarbonyl,            pyridyl,            -   C₁₋₆ alkyl optionally substituted by cyano or mono- di-                or tri-halogen,            -   and            -   C₁₋₆alkoxy optionally substituted by cyano, carboxy,                amino, N—(C₁₋₆ alkyl)amino, N,N-di(C₁₋₆alkyl)amino,                aminocarbonyl, N—(C₁₋₆alkyl)aminocarbonyl,                N,N-di(C₁₋₆alkyl)aminocarbonyl or mono-, di- or                tri-halogen;    -   R² represents hydroxy, halogen, nitro, cyano, amino,        N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino,        N-(hydroxyC₁₋₆alkyl)amino,        N-(hydroxyC₁₋₆alkyl)-N—(C₁₋₆alkyl)amino, C₁₋₆ acyloxy, aminoC₁₋₆        acyloxy, C₂₋₆alkenyl, aryl,        -   a 5-7 membered saturated or unsaturated heterocyclic ring            having 1 to 3 heteroatoms selected from the group consisting            O, S and N, and optionally substituted by        -   hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, oxo, amino, amino            C₁₋₆alkyl, N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino,            N—(C₁₋₆ acyl)amino, N—(C₁₋₆alkyl)carbonylamino, phenyl,            phenyl C₁₋₆ alkyl, carboxy, C₁₋₆alkoxycarbonyl,            aminocarbonyl, N—(C₁₋₆alkyl)aminocarbonyl, or            N,N-di(C₁₋₆alkyl)amino, —C(O)—R²⁰        -   wherein        -   R²⁰ represents C₁₋₆ alkyl, C₁₋₆ alkoxy, amino,            N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆            acyl)amino, or a 5-7 membered saturated or unsaturated            heterocyclic ring having 1 to 3 heteroatoms selected from            the group consisting O, S and N, and optionally substituted            by C₁₋₆ alkyl, C₁₋₆ alkoxy, oxo, amino, N—(C₁₋₆alkyl)amino,            N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆ acyl)amino, phenyl, or            benzyl,            -   C₁₋₆ alkyl optionally substituted by R²¹,            -   or            -   C₁₋₆ alkoxy optionally substituted by R²¹,            -   wherein            -   R²¹ represents cyano, mono-, di or tri-halogen, hydroxy,                amino, N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino,                N-(hydroxyC₁₋₆ alkyl)amino, N-(halophenylC₁₋₆                alkyl)amino, amino C₂₋₆ alkylenyl, C₁₋₆ alkoxy,                hydroxyC₁₋₆ alkoxy, —C(O)—R²⁰¹, —NHC(O)—R²⁰¹,                C₃₋₈cycloalkyl, isoindolino, phthalimidyl,                2-oxo-1,3-oxazolidinyl, aryl or a 5 or 6 membered                saturated or unsaturated heterocyclic ring having 1 to 4                heteroatoms selected from the group consisting O, S and                N, and optionally substituted by hydroxy, C₁₋₆ alkyl,                C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, hydroxyC₁₋₆ alkoxy,                oxo, amino, aminoC₁₋₆alkyl, N—(C₁₋₆alkyl)amino,                N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆ acyl)amino, or benzyl,                -   wherein                -   R²⁰¹ represents hydroxy, amino, N—(C₁₋₆alkyl)amino,                    N,N-di(C₁₋₆alkyl)amino, N-(halophenylC₁₋₆                    alkyl)amino, C₁₋₆alkyl, aminoC₁₋₆ alkyl, aminoC₂₋₆                    alkylenyl, C₁₋₆ alkoxy, a 5 or 6 membered saturated                    or unsaturated heterocyclic ring having 1 to 4                    heteroatoms selected from the group consisting O, S                    and N, and optionally substituted by hydroxy, C₁₋₆                    alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, hydroxyC₁₋₆                    alkoxy, oxo, amino, N—(C₁₋₆alkyl)amino,                    N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆ acyl)amino or                    benzyl;    -   R³ represents hydrogen, halogen, aminocarbonyl, or C₁₋₆ alkyl        optionally substituted by aryl C₁₋₆ alkoxy or mono-, di- or        tri-halogen;    -   R⁴ represents hydrogen or C₁₋₆ alkyl;    -   R⁵ represents hydrogen or C₁₋₆ alkyl; and    -   R⁶ represents halogen, hydrogen or C₁₋₆ alkyl,

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, for the preparation of a medicament for the treatment orprophylaxis of multiple myeloma, as a sole agent or in combination withone or more other active ingredients.

In a particular embodiment of the above-mentioned first embodiment, thepresent invention relates to the use of a compound selected from thefollowing list for the preparation of a medicament for the treatment orprophylaxis of multiple myeloma, as a sole agent or in combination withone or more other active ingredients:

N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;

2-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-pyridin-3-ylethylenol;

N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;

6-(acetamido)-N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;

N-{5-[2-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-hydroxyvinyl]pyridin-2-yl}acetamide;

2-({5-[2-hydroxy-2-pyridin-3-ylvinyl]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl}oxy)-N,N-dimethylacetamide;

2-[7-methoxy-8-(tetrahydro-2H-pyran-2-ylmethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-pyridin-3-ylethylenol;

2-[8-(2-hydroxyethoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-pyridin-3-ylethylenol;

({5-[2-hydroxy-2-pyridin-3-ylvinyl]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl}oxy)aceticacid;

4-({5-[2-hydroxy-2-pyridin-3-ylvinyl]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl}oxy)butanoicacid;

({5-[2-hydroxy-2-pyridin-3-ylvinyl]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl}oxy)acetonitrile;

2-[7-methoxy-8-(2H-tetrazol-5-ylmethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-pyridin-3-ylethylenol;

2-[7-methoxy-8-(4-morpholin-4-yl-4-oxobutoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-pyridin-3-ylethylenol;

5-[1-hydroxy-2-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)vinyl]pyridin-3-ol;

N-(2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-5-hydroxynicotinamide;

6-(acetamido)-N-(7,9-dimethoxy-8-methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;

N-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-5-hydroxynicotinamide;

5-hydroxy-N-(7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;

N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-5-[(4-methoxybenzyl)oxy]nicotinamide;

N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-5-hydroxynicotinamide;

5-hydroxy-N-8-(trifluoromethyl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;

N-{8-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;

N-(7-bromo-8-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;

6-amino-N-(8-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;

1-(1H-benzimidazol-5-yl)-2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)ethylenol;

2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-(2,4-dimethyl-1,3-thiazol-5-yl)ethylenol;

N-(9-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;

N-(8-bromo-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;

N-(8-bromo-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;

N-(8-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;

N-(8-methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;

N-[8-(trifluoromethyl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1H-benzimidazole-5-carboxamide;

N-(7-fluoro-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;

N-(7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;

N-(8-chloro-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;

6-(acetamido)-N-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;

1-(1H-benzimidazol-5-yl)-2-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)ethylenol;

N-{5-[1-hydroxy-2-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)vinyl]pyridin-2-yl}acetamide;

6-methyl-N-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;

1-(1H-benzimidazol-5-yl)-2-[8-(4-methylpiperazin-1-yl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]ethylenol;

N-(2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-3H-imidazo[4,5-b]pyridine-6-carboxamide;

N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-3H-imidazo[4,5-b]pyridine-6-carboxamide;

N-[7-(trifluoromethyl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1H-benzimidazole-5-carboxamide;

N-(7,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;

N-{5-[2-(7,9-dimethoxy-8-methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-hydroxyvinyl]pyridin-2-yl}acetamide;

N-{5-[2-(7-bromo-9-methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-hydroxyvinyl]pyridin-2-yl}acetamide;and

2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-pyridin-3-ylethylenol;

Another embodiment of the present invention encompasses the use of acompound having the formula (I):

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, in which:

-   -   R¹ represents —(CH₂)_(n)—(CHR⁴)—(CH₂)_(m)—N(R⁵)(R⁵′);    -   R² represents a heteroaryl optionally substituted with 1, 2 or 3        R⁶ groups;    -   R³ represents alkyl or cycloalkyl;    -   R⁴ represents hydrogen, hydroxy or alkoxy; and    -   R⁵ and R⁵′ may be the same or different and represent        independently, hydrogen, alkyl, cycloalkylalklyl, or alkoxyalkyl        or R⁵ and R⁵′ may be taken together with the nitrogen atom to        which they are bound to form a 3-7 membered nitrogen containing        heterocyclic ring optionally containing at least one additional        heteroatom selected from oxygen, nitrogen or sulfur and which        may be optionally substituted with 1 or more R^(6′) groups, or        R⁴ and R⁵ may be taken together with the atoms to which they are        bound to form a 5-6 membered nitrogen containing heterocyclic        ring optionally containing 1 or more nitrogen, oxygen or sulfur        atoms and which may be optionally substituted with 1 or more        R^(6′) groups;

each occurrence of R⁶ may be the same or different and is independentlyhalogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalklyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic ring,heterocyclylalkyl, alkyl-OR⁷, alkyl-SR⁷, alkyl-N(R⁷)(R^(7′)),alkyl-COR⁷, —CN, —COOR⁷, —CON(R⁷)(R^(7′)), —OR⁷, —SR⁷, —N(R⁷)(R^(7′)),or —NR⁷COR⁷ each of which may be optionally substituted with 1 or moreR⁸ groups;

each occurrence of R^(6′) may be the same or different and isindependently alkyl, cycloalkylalklyl, or alkyl-OR⁷;

each occurrence of R⁷ and R^(7′) may be the same or different and isindependently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalklyl, cycloalkenyl, aryl, arylalkyl, heteroaryl,heterocyclic ring, heterocyclylalkyl, or heteroarylalkyl;

each occurrence of R⁸ is independently nitro, hydroxy, cyano, formyl,acetyl, halogen, amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,cycloalkylalklyl, cycloalkenyl, aryl, arylalkyl, heteroaryl,heterocyclic ring, heterocyclylalkyl, or heteroarylalkyl;

n is an integer from 1-4 and m is an integer from 0-4 with the provisothat when when R⁴ and R⁵ are taken together with the atoms to which theyare bound to form a 5-6 membered nitrogen containing ring, n+m≦4;

for the preparation of a medicament for the treatment or prophylaxis ofmultiple myeloma.

In a preferred embodiment, the invention encompasses the use of acompound of Formula (I), wherein R² is a nitrogen containing heteroaryloptionally substituted with 1, 2 or 3 R⁶ groups,

for the preparation of a medicament for the treatment or prophylaxis ofmultiple myeloma.

In another preferred embodiment, the invention encompasses the use of acompound of Formula (I), wherein R⁵ and R^(5′) are independently alkyl,

for the preparation of a medicament for the treatment or prophylaxis ofmultiple myeloma.

In still another preferred embodiment, the invention encompasses the useof a compound of Formula (I), wherein R⁵ and R^(5′) are taken togetherwith the nitrogen atom to which they are bound to form a 5-6 memberednitrogen containing heterocyclic ring containing at least one additionalheteroatom selected from oxygen, nitrogen or sulfur and which may beoptionally substituted with 1 or more R^(6′) groups,

for the preparation of a medicament for the treatment or prophylaxis ofmultiple myeloma.

In yet another preferred embodiment, the invention encompasses the useof a compound of Formula (I), wherein R⁴ is hydroxyl,

for the preparation of a medicament for the treatment or prophylaxis ofmultiple myeloma.

In another preferred embodiment, the invention encompasses the use of acompound of Formula (I), wherein R⁴ and R⁵ are taken together with theatoms to which they are bound to form a 5-6 membered nitrogen containingheterocyclic ring optionally containing 1 or more nitrogen, oxygen orsulfur atoms and which may be optionally substituted with 1 or more R⁶groups, for the preparation of a medicament for the treatment orprophylaxis of multiple myeloma.

In yet another preferred embodiment, the invention encompasses the useof a compound of Formula (I), wherein R³ is methyl,

for the preparation of a medicament for the treatment or prophylaxis ofmultiple myeloma.

In still another preferred embodiment, the invention encompasses the useof a compound of Formula (I), wherein R² is pyridine, pyridazine,pyrimidine, pyrazine, pyrole, oxazole, thiazole, furan or thiophene,optionally substituted with 1, 2 or 3 R⁶ groups; more preferablypyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole or thiazole,optionally substituted with 1, 2 or 3 R⁶ groups,

for the preparation of a medicament for the treatment or prophylaxis ofmultiple myeloma.

In a distinct embodiment, the invention encompasses the use of acompound of formula (Ia)

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, wherein R² is as defined above,

for the preparation of a medicament for the treatment or prophylaxis ofmultiple myeloma.

In another distinct embodiment, the invention encompasses the use of acompound of formula (Ib):

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, wherein R² is as defined above,

for the preparation of a medicament for the treatment or prophylaxis ofmultiple myeloma.

In still another distinct embodiment, the invention encompasses the useof a compound of formula (Ic):

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, wherein R² is as defined above,

for the preparation of a medicament for the treatment or prophylaxis ofmultiple myeloma.

In yet another distinct embodiment, the invention encompasses the use ofa compound of the formula (Id):

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, wherein R² and R⁴ are as defined above,

for the preparation of a medicament for the treatment or prophylaxis ofmultiple myeloma.

In yet another distinct embodiment, the invention encompasses the use ofa compound of the formula (Ie):

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, wherein R² and R⁴ are as defined above,

for the preparation of a medicament for the treatment or prophylaxis ofmultiple myeloma.

In a preferred embodiment, the invention encompasses the use of acompound of formula (I)-(V), wherein R² is pyridine, pyridazine,pyrimidine, pyrazine, pyrole, oxazole, thiazole, furan or thiophene,optionally substituted with 1, 2 or 3 R⁶ groups; more preferably whereinR² is pyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole orthiazole, optionally substituted with 1, 2 or 3 R⁶ groups,

for the preparation of a medicament for the treatment or prophylaxis ofmultiple myeloma.

In still another preferred embodiment, the invention encompasses the useof a compound having the formula:

-   -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;    -   N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxyl-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;    -   N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxyl-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-2,4-dimethyl-1,3-thiazole-5-carboxamide;    -   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1,3-thiazole-5-carboxamide;    -   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]isonicotinamide;    -   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-4-methyl-1,3-thiazole-5-carboxamide;    -   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-4-propylpyrimidine-5-carboxamide;    -   N-{8-[2-(4-ethylmorpholin-2-yl)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;    -   N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide;    -   N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxyl-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;    -   N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxyl-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;    -   N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide        1-oxide;    -   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-(2-pyrrolidin-1-ylethyl)nicotinamide;    -   6-(cyclopentylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    -   N-[8-(2-hydroxy-3-morpholin-4-ylpropoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    -   N-{7-methoxy-8-[3-(3-methylmorpholin-4-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;    -   N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;    -   N-(8-{2-[4-(cyclobutylmethyl)morpholin-2-yl]ethoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;    -   N-(7-methoxy-8-{2-[4-(2-methoxyethyl)morpholin-2-yl]ethoxy}-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;    -   N-{8-[(4-ethylmorpholin-2-yl)methoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;    -   N-(7-methoxy-8-{[4-(2-methoxyethyl)morpholin        -2-yl]methoxy}-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;    -   N-{7-methoxy-8-[(4-methylmorpholin-2-yl)methoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-4-carboxamide;    -   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-4-carboxamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-methyl-1H-imidazole-4-carboxamide;    -   rel-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide;    -   rel-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-6-methylnicotinamide;    -   rel-6-acetamido-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-methyl-1H-imidazole-5-carboxamide;    -   6-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-methylnicotinamide;    -   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-4-methylpyrimidine-5-carboxamide;    -   6-amino-5-bromo-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    -   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1,3-oxazole-5-carboxamide;    -   N-[7-methoxy-8-(morpholin-2-ylmethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    -   2-{[2-(dimethylamino)ethyl]amino}-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide;    -   2-amino-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}-1,3-thiazole-5-carboxamide;    -   rel-2-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide;    -   rel-6-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;    -   2-[(2-hydroxyethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-[(3-methoxypropyl)amino]pyrimidine-5-carboxamide;    -   2-amino-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-[(3-morpholin-4-ylpropyl)amino]pyrimidine-5-carboxamide;    -   2-[(2-methoxyethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;    -   2-{[2-(dimethylamino)ethyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;    -   6-amino-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-pyrrolidin-1-ylpyrimidine-5-carboxamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-morpholin-4-ylpyrimidine-5-carboxamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-piperazin-1-ylnicotinamide        hydrochloride;    -   6-[(3S)-3-aminopyrrolidin-1-yl]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide        hydrochloride hydrate;    -   6-[(3R)-3-aminopyrrolidin-1-yl]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide        hydrochloride;    -   6-[(4-fluorobenzyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    -   6-[(2-furylmethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    -   6-[(2-methoxyethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-(1H-pyrrol-1-yl)nicotinamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-morpholin-4-ylnicotinamide;    -   N-{7-methoxy-8-[3-(methylamino)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;    -   6-[(2,2-dimethylpropanoyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    -   6-[(cyclopropylcarbonyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-(2,2,2-trifluoroethoxy)nicotinamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-(trifluoromethyl)nicotinamide;    -   6-(isobutyrylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    -   N-{7-methoxy-8-[3-(4-methylpiperazin-1-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-{[(methylamino)carbonyl]amino}-1,3-thiazole-4-carboxamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-{[(methylamino)carbonyl]amino}nicotinamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-(methylamino)-1,3-thiazole-4-carboxamide;    -   N-[7-methoxy-8-(2-morpholin-4-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    -   N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}-2,4-dimethyl-1,3-thiazole-5-carboxamide;    -   N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}-6-methylnicotinamide;    -   6-{[(isopropylamino)carbonyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-pyrrolidin-1-ylnicotinamide;    -   6-(dimethylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    -   N-[7-methoxy-8-(3-piperidin-1-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    -   N-[7-methoxy-8-(2-pyrrolidin-1-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    -   N-[7-methoxy-8-(2-piperidin-1-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    -   6-{[(ethylamino)carbonyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    -   6-fluoro-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    -   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1,3-oxazole-4-carboxamide;    -   2-(ethylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1,3-thiazole-4-carboxamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrazine-2-carboxamide;    -   N-[8-(2-aminoethoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    -   6-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]isonicotinamide;    -   N-{8-[3-(diethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;    -   N-{8-[2-(diisopropylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;    -   N-{8-[2-(diethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;    -   N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;    -   N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-(methylamino)pyrimidine-5-carboxamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-(methylthio)pyrimidine-5-carboxamide;    -   N-[8-(3-aminopropoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide        trifluoroacetate;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]thiophene-2-carboxamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2,4-dimethyl-1,3-thiazole-5-carboxamide;    -   2-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-3-furamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]thiophene-3-carboxamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-methyl-1,3-thiazole-4-carboxamide;    -   6-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    -   5-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-methylnicotinamide;    -   6-(acetylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, for the preparation of a medicament for the treatment orprophylaxis of multiple myeloma.

In a preferred embodiment, the invention encompasses the use of acompound having the formula:

-   -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-methylnicotinamide;    -   5-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2,4-dimethyl-1,3-thiazole-5-carboxamide;    -   N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;    -   N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;    -   6-{[(isopropylamino)carbonyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    -   N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}-2,4-dimethyl-1,3-thiazole-5-carboxamide;    -   N-[7-methoxy-8-(2-morpholin-4-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    -   rel-6-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxyl-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;    -   rel-2-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxyl-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide;    -   2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;    -   N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide;    -   N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, for the preparation of a medicament for the treatment orprophylaxis of multiple myeloma.

Where there is a discrepancy between the chemical name and the chemicalstructure depicted, the chemical structure depicted takes precedenceover the chemical name given.

Without being bound by theory or mechanism, the compounds of the presentinvention display surprising activity for the inhibition ofphosphatidylinositol-3-kinase and chemical and structural stability overthose compounds of the prior art. It is believed that this surprisingactivity is based on the chemical structure of the compounds, inparticular the basicity of the compounds as a result of R¹ being aminooptionally substituted with R⁵ and R^(5′). Further, the appropriatechoice of R³ and R² provide the necessary activity against theappropriate isoforms to allow for activity in vivo.

Definitions

The term ‘alkyl’ refers to a straight or branched hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, containingsolely of carbon and hydrogen atoms, containing no unsaturation, havingfrom one to eight carbon atoms, and which is attached to the rest of themolecule by a single bond, such as illustratively, methyl, ethyl,n-propyl 1-methylethyl(isopropyl), n-butyl, n-pentyl, and1,1-dimethylethyl(t-butyl).

The term “alkenyl ” refers to an aliphatic hydrocarbon group containinga carbon-carbon double bond and which may be a straight or branched orbranched chain having about 2 to about 10 carbon atoms, e.g., ethenyl,1-propenyl, 2-propenyl(allyl), iso-propenyl, 2-methyl-I-propenyl,1-butenyl, 1- and butenyl.

The term “alkynyl” refers to a straight or branched chain hydrocarbonylradicals having at least one carbon-carbon triple bond, and having inthe range of about 2 up to 12 carbon atoms (with radicals having in therange of about 2 up to 10 carbon atoms presently being preferred) e.g.,ethynyl.

The term “alkoxy” denotes an alkyl group as defined herein attached viaoxygen linkage to the rest of the molecule. Representative examples ofthose groups are methoxy and ethoxy.

The term “alkoxyakyl” denotes an alkoxy group as defined herein attachedvia oxygen linkage to an alkyl group which is then attached to the mainstructure at any carbon from alkyl group that results in the creation ofa stable structure the rest of the molecule. Representative examples ofthose groups are —CH₂OCH₃, —CH₂OC₂H₅.

The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ringsystem of about 3 to 12 carbon atoms such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and examples of multicyclic cycloalkyl groupsinclude perhydronapththyl, adamantyl and norbornyl groups bridged cyclicgroup or sprirobicyclic groups e.g sprio(4,4)non-2-yl.

The term “cycloalkylalkyl” refers to cyclic ring-containing radicalscontaining in the range of about about 3 up to 8 carbon atoms directlyattached to alkyl group which is then also attached to the mainstructure at any carbon from the alkyl group that results in thecreation of a stable structure such as cyclopropylmethyl,cyclobuyylethyl, cyclopentylethyl.

The term “aryl” refers to aromatic radicals having in the range of 6 upto 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl,biphenyl.

The term “arylalkyl” refers to an aryl group as defined herein directlybonded to an alkyl group as defined herein which is then attached to themain structure at any carbon from alkyl group that results in thecreation of a stable structure the rest of the molecule. e.g., —CH₂C₆H₅,—C₂H₅C₆H₅.

The term “heterocyclic ring” refers to a stable 3- to 15 membered ringradical which consists of carbon atoms and from one to five heteroatomsselected from the group consisting of nitrogen, phosphorus, oxygen andsulfur. For purposes of this invention, the heterocyclic ring radicalmay be a monocyclic, bicyclic or tricyclic ring system, which mayinclude fused, bridged or spiro ring systems, and the nitrogen,phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ringradical may be optionally oxidized to various oxidation states. Inaddition, the nitrogen atom may be optionally quaternized; and the ringradical may be partially or fully saturated (i.e., heteroaromatic orheteroaryl aromatic). Examples of such heterocyclic ring radicalsinclude, but are not limited to, azetidinyl, acridinyl, benzodioxolyl,benzodioxanyl, benzofurnyl, carbazolyl cinnolinyl dioxolanyl,indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl,phenothiazinyl, phenoxazinyl, phthalazil, pyridyl, pteridinyl, purinyl,quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl,imidazolyl tetrahydroisouinolyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl,azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinylpyridazinyl, oxazolyl oxazolinyl oxasolidinyl, triazolyl, indanyl,isoxazolyl, isoxasolidinyl, morpholinyl, thiazolyl, thiazolinyl,thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl,isoindolyl, indolinyl, isoindolinyl, octahydroindolyl,octahydroisoindolyl quinolyl, isoquinolyl, decahydroisoquinolyl,benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl,benzooxazolyl, furyl, tetrahydrofurtyl, tetrahydropyranyl, thienyl,benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide thiamorpholinylsulfone, dioxaphospholanyl, oxadiazolyl, chromanyl, isochromanyl.

The term “heteroaryl” refers to heterocyclic ring radical as definedherein which are aromatic. The heteroaryl ring radical may be attachedto the main structure at any heteroatom or carbon atom that results inthe creation of a stable structure.

The heterocyclic ring radical may be attached to the main structure atany heteroatom or carbon atom that results in the creation of a stablestructure.

The term “heteroarylalkyl” refers to heteroaryl ring radical as definedherein directly bonded to alkyl group. The heteroarylalkyl radical maybe attached to the main structure at any carbon atom from alkyl groupthat results in the creation of a stable structure.

The term “heterocyclyl” refers to a heterocylic ring radical as definedherein. The heterocylyl ring radical may be attached to the mainstructure at any heteroatom or carbon atom that results in the creationof a stable structure.

The term “heterocyclylalkyl” refers to a heterocylic ring radical asdefined herein directly bonded to alkyl group. The heterocyclylalkylradical may be attached to the main structure at carbon atom in thealkyl group that results in the creation of a stable structure.

The term “carbonyl” refers to an oxygen atom bound to a carbon atom ofthe molecule by a double bond.

The term “halogen” refers to radicals of fluorine, chlorine, bromine andiodine.

Where the plural form of the word compounds, salts, polymorphs,hydrates, solvates and the like, is used herein, this is taken to meanalso a single compound, salt, polymorph, isomer, hydrate, solvate or thelike.

The compounds of this invention may contain one or more asymmetriccenters, depending upon the location and nature of the varioussubstituents desired. Asymmetric carbon atoms may be present in the (R)or (S) configuration, resulting in racemic mixtures in the case of asingle asymmetric center, and diastereomeric mixtures in the case ofmultiple asymmetric centers. In certain instances, asymmetry may also bepresent due to restricted rotation about a given bond, for example, thecentral bond adjoining two substituted aromatic rings of the specifiedcompounds. Substituents on a ring may also be present in either cis ortrans form. It is intended that all such configurations (includingenantiomers and diastereomers), are included within the scope of thepresent invention. Preferred compounds are those, which produce the moredesirable biological activity. Separated, pure or partially purifiedisomers and stereoisomers or racemic or diastereomeric mixtures of thecompounds of this invention are also included within the scope of thepresent invention. The purification and the separation of such materialscan be accomplished by standard techniques known in the art.

The present invention also relates to useful forms of the compounds asdisclosed herein, such as pharmaceutically acceptable salts,co-precipitates, metabolites, hydrates, solvates and prodrugs of all thecompounds of examples. The term “pharmaceutically acceptable salt”refers to a relatively non-toxic, inorganic or organic acid additionsalt of a compound of the present invention. For example, see S. M.Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19.Pharmaceutically acceptable salts include those obtained by reacting themain compound, functioning as a base, with an inorganic or organic acidto form a salt, for example, salts of hydrochloric acid, sulfuric acid,phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalicacid, maleic acid, succinic acid and citric acid. Pharmaceuticallyacceptable salts also include those in which the main compound functionsas an acid and is reacted with an appropriate base to form, e.g.,sodium, potassium, calcium, magnesium, ammonium, and chorine salts.Those skilled in the art will further recognize that acid addition saltsof the claimed compounds may be prepared by reaction of the compoundswith the appropriate inorganic or organic acid via any of a number ofknown methods. Alternatively, alkali and alkaline earth metal salts ofacidic compounds of the invention are prepared by reacting the compoundsof the invention with the appropriate base via a variety of knownmethods.

Representative salts of the compounds of this invention include theconventional non-toxic salts and the quaternary ammonium salts which areformed, for example, from inorganic or organic acids or bases by meanswell known in the art. For example, such acid addition salts includeacetate, adipate, alginate, ascorbate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide,iodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate,mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate,nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate,picrate, pivalate, propionate, succinate, sulfonate, sulfate, tartrate,thiocyanate, tosylate, and undecanoate.

Base salts include alkali metal salts such as potassium and sodiumsalts, alkaline earth metal salts such as calcium and magnesium salts,and ammonium salts with organic bases such as dicyclohexylamine andN-methyl-D-glucamine. Additionally, basic nitrogen containing groups maybe quaternized with such agents as lower alkyl halides such as methyl,ethyl, propyl, or butyl chlorides, bromides and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl sulfate, or diamyl sulfates,long chain halides such as decyl, lauryl, myristyl and strearylchlorides, bromides and iodides, aralkyl halides like benzyl andphenethyl bromides and others.

A solvate for the purpose of this invention is a complex of a solventand a compound of the invention in the solid state. Exemplary solvateswould include, but are not limited to, complexes of a compound of theinvention with ethanol or methanol. Hydrates are a specific form ofsolvate wherein the solvent is water.

The synthesis of the compounds listed above is described in theInternational Patent Application No. PCT/EP2003/010377, published as WO2004/029055 A1, and in International Patent Application No.PCT/US2007/024985, published as WO 2008/070150, both of which are herebyincorporated herein in their entirety by reference.

Pharmaceutical Compositions of the Compounds of the Invention

This invention also relates to pharmaceutical compositions containingone or more compounds of the present invention. These compositions canbe utilized to achieve the desired pharmacological effect byadministration to a patient in need thereof. A patient, for the purposeof this invention, is a mammal, including a human, in need of treatmentfor the particular condition or disease. Therefore, the presentinvention includes pharmaceutical compositions that are comprised of apharmaceutically acceptable carrier and a pharmaceutically effectiveamount of a compound, or salt thereof, of the present invention. Apharmaceutically acceptable carrier is preferably a carrier that isrelatively non-toxic and innocuous to a patient at concentrationsconsistent with effective activity of the active ingredient so that anyside effects ascribable to the carrier do not vitiate the beneficialeffects of the active ingredient. A pharmaceutically effective amount ofcompound is preferably that amount which produces a result or exerts aninfluence on the particular condition being treated. The compounds ofthe present invention can be administered withpharmaceutically-acceptable carriers well known in the art using anyeffective conventional dosage unit forms, including immediate, slow andtimed release preparations, orally, parenterally, topically, nasally,ophthalmically, optically, sublingually, rectally, vaginally, and thelike.

For oral administration, the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, troches, lozenges,melts, powders, solutions, suspensions, or emulsions, and may beprepared according to methods known to the art for the manufacture ofpharmaceutical compositions. The solid unit dosage forms can be acapsule that can be of the ordinary hard- or soft-shelled gelatin typecontaining, for example, surfactants, lubricants, and inert fillers suchas lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of this invention may be tabletedwith conventional tablet bases such as lactose, sucrose and cornstarchin combination with binders such as acacia, corn starch or gelatin,disintegrating agents intended to assist the break-up and dissolution ofthe tablet following administration such as potato starch, alginic acid,corn starch, and guar gum, gum tragacanth, acacia, lubricants intendedto improve the flow of tablet granulation and to prevent the adhesion oftablet material to the surfaces of the tablet dies and punches, forexample talc, stearic acid, or magnesium, calcium or zinc stearate,dyes, coloring agents, and flavoring agents such as peppermint, oil ofwintergreen, or cherry flavoring, intended to enhance the aestheticqualities of the tablets and make them more acceptable to the patient.Suitable excipients for use in oral liquid dosage forms includedicalcium phosphate and diluents such as water and alcohols, forexample, ethanol, benzyl alcohol, and polyethylene alcohols, either withor without the addition of a pharmaceutically acceptable surfactant,suspending agent or emulsifying agent. Various other materials may bepresent as coatings or to otherwise modify the physical form of thedosage unit. For instance tablets, pills or capsules may be coated withshellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of anaqueous suspension. They provide the active ingredient in admixture witha dispersing or wetting agent, a suspending agent and one or morepreservatives. Suitable dispersing or wetting agents and suspendingagents are exemplified by those already mentioned above. Additionalexcipients, for example those sweetening, flavoring and coloring agentsdescribed above, may also be present.

The pharmaceutical compositions of this invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oilsuch as liquid paraffin or a mixture of vegetable oils. Suitableemulsifying agents may be (1) naturally occurring gums such as gumacacia and gum tragacanth, (2) naturally occurring phosphatides such assoy bean and lecithin, (3) esters or partial esters derived form fattyacids and hexitol anhydrides, for example, sorbitan monooleate, (4)condensation products of said partial esters with ethylene oxide, forexample, polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening and flavoring agents.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil such as, for example, arachis oil, olive oil, sesameoil or coconut oil, or in a mineral oil such as liquid paraffin. Theoily suspensions may contain a thickening agent such as, for example,beeswax, hard paraffin, or cetyl alcohol. The suspensions may alsocontain one or more preservatives, for example, ethyl or n-propylp-hydroxybenzoate; one or more coloring agents; one or more flavoringagents; and one or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, and preservative, such asmethyl and propyl parabens and flavoring and coloring agents.

The compounds of this invention may also be administered parenterally,that is, subcutaneously, intravenously, intraocularly, intrasynovially,intramuscularly, or interperitoneally, as injectable dosages of thecompound in preferably a physiologically acceptable diluent with apharmaceutical carrier which can be a sterile liquid or mixture ofliquids such as water, saline, aqueous dextrose and related sugarsolutions, an alcohol such as ethanol, isopropanol, or hexadecylalcohol, glycols such as propylene glycol or polyethylene glycol,glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4-methanol, etherssuch as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acidester or, a fatty acid glyceride, or an acetylated fatty acid glyceride,with or without the addition of a pharmaceutically acceptable surfactantsuch as a soap or a detergent, suspending agent such as pectin,carbomers, methycellulose, hydroxypropylmethylcellulose, orcarboxymethylcellulose, or emulsifying agent and other pharmaceuticaladjuvants.

Illustrative of oils which can be used in the parenteral formulations ofthis invention are those of petroleum, animal, vegetable, or syntheticorigin, for example, peanut oil, soybean oil, sesame oil, cottonseedoil, corn oil, olive oil, petrolatum and mineral oil. Suitable fattyacids include oleic acid, stearic acid, isostearic acid and myristicacid. Suitable fatty acid esters are, for example, ethyl oleate andisopropyl myristate. Suitable soaps include fatty acid alkali metal,ammonium, and triethanolamine salts and suitable detergents includecationic detergents, for example dimethyl dialkyl ammonium halides,alkyl pyridinium halides, and alkylamine acetates; anionic detergents,for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether,and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents,for example, fatty amine oxides, fatty acid alkanolamides, andpoly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxidecopolymers; and amphoteric detergents, for example,alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammoniumsalts, as well as mixtures.

The parenteral compositions of this invention will typically containfrom about 0.5% to about 25% by weight of the active ingredient insolution. Preservatives and buffers may also be used advantageously. Inorder to minimize or eliminate irritation at the site of injection, suchcompositions may contain a non-ionic surfactant having ahydrophile-lipophile balance (HLB) preferably of from about 12 to about17. The quantity of surfactant in such formulation preferably rangesfrom about 5% to about 15% by weight. The surfactant can be a singlecomponent having the above HLB or can be a mixture of two or morecomponents having the desired HLB.

Illustrative of surfactants used in parenteral formulations are theclass of polyethylene sorbitan fatty acid esters, for example, sorbitanmonooleate and the high molecular weight adducts of ethylene oxide witha hydrophobic base, formed by the condensation of propylene oxide withpropylene glycol.

The pharmaceutical compositions may be in the form of sterile injectableaqueous suspensions. Such suspensions may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents such as, for example, sodium carboxymethylcellulose,methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents which may be a naturally occurring phosphatide such aslecithin, a condensation product of an alkylene oxide with a fatty acid,for example, polyoxyethylene stearate, a condensation product ofethylene oxide with a long chain aliphatic alcohol, for example,heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxidewith a partial ester derived form a fatty acid and a hexitol such aspolyoxyethylene sorbitol monooleate, or a condensation product of anethylene oxide with a partial ester derived from a fatty acid and ahexitol anhydride, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent. Diluents and solvents that may be employed are, for example,water, Ringer's solution, isotonic sodium chloride solutions andisotonic glucose solutions. In addition, sterile fixed oils areconventionally employed as solvents or suspending media. For thispurpose, any bland, fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid can be usedin the preparation of injectables.

A composition of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritationexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are, for example, cocoa butter and polyethyleneglycol.

Another formulation employed in the methods of the present inventionemploys transdermal delivery devices (“patches”). Such transdermalpatches may be used to provide continuous or discontinuous infusion ofthe compounds of the present invention in controlled amounts. Theconstruction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art (see, e.g., U.S. Pat. No.5,023,252, issued Jun. 11, 1991, incorporated herein by reference). Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents.

Controlled release formulations for parenteral administration includeliposomal, polymeric microsphere and polymeric gel formulations that areknown in the art.

It may be desirable or necessary to introduce the pharmaceuticalcomposition to the patient via a mechanical delivery device. Theconstruction and use of mechanical delivery devices for the delivery ofpharmaceutical agents is well known in the art. Direct techniques for,for example, administering a drug directly to the brain usually involveplacement of a drug delivery catheter into the patient's ventricularsystem to bypass the blood-brain barrier. One such implantable deliverysystem, used for the transport of agents to specific anatomical regionsof the body, is described in U.S. Pat. No. 5,011,472, issued Apr. 30,1991.

The compositions of the invention can also contain other conventionalpharmaceutically acceptable compounding ingredients, generally referredto as carriers or diluents, as necessary or desired. Conventionalprocedures for preparing such compositions in appropriate dosage formscan be utilized. Such ingredients and procedures include those describedin the following references, each of which is incorporated herein byreference: Powell, M. F. et al, “Compendium of Excipients for ParenteralFormulations” PDA Journal of Pharmaceutical Science & Technology 1998,52(5), 238-311; Strickley, R. G “Parenteral Formulations of SmallMolecule Therapeutics Marketed in the United States (1999)-Part-1” PDAJournal of Pharmaceutical Science & Technology 1999, 53(6), 324-349; andNema, S. et al, “Excipients and Their Use in Injectable Products” PDAJournal of Pharmaceutical Science & Technology 1997, 51(4), 166-171.

Commonly used pharmaceutical ingredients that can be used as appropriateto formulate the composition for its intended route of administrationinclude:

acidifying agents (examples include but are not limited to acetic acid,citric acid, fumaric acid, hydrochloric acid, nitric acid);

alkalinizing agents (examples include but are not limited to ammoniasolution, ammonium carbonate, diethanolamine, monoethanolamine,potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide,triethanolamine, trolamine);

adsorbents (examples include but are not limited to powdered celluloseand activated charcoal);

aerosol propellants (examples include but are not limited to carbondioxide, CCl₂F₂, F₂ClC—CClF₂ and CClF₃)

air displacement agents (examples include but are not limited tonitrogen and argon);

antifungal preservatives (examples include but are not limited tobenzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben,sodium benzoate);

antimicrobial preservatives (examples include but are not limited tobenzalkonium chloride, benzethonium chloride, benzyl alcohol,cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol,phenylmercuric nitrate and thimerosal);

antioxidants (examples include but are not limited to ascorbic acid,ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene,hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate,sodium bisulfite, sodium formaldehyde sulfoxylate, sodiummetabisulfite);

binding materials (examples include but are not limited to blockpolymers, natural and synthetic rubber, polyacrylates, polyurethanes,silicones, polysiloxanes and styrene-butadiene copolymers);

buffering agents (examples include but are not limited to potassiummetaphosphate, dipotassium phosphate, sodium acetate, sodium citrateanhydrous and sodium citrate dihydrate)

carrying agents (examples include but are not limited to acacia syrup,aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orangesyrup, syrup, corn oil, mineral oil, peanut oil, sesame oil,bacteriostatic sodium chloride injection and bacteriostatic water forinjection)

chelating agents (examples include but are not limited to edetatedisodium and edetic acid)

colorants (examples include but are not limited to FD&C Red No. 3, FD&CRed No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&COrange No. 5, D&C Red No. 8, caramel and ferric oxide red);

clarifying agents (examples include but are not limited to bentonite);

emulsifying agents (examples include but are not limited to acacia,cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitanmonooleate, polyoxyethylene 50 monostearate);

encapsulating agents (examples include but are not limited to gelatinand cellulose acetate phthalate)

flavorants (examples include but are not limited to anise oil, cinnamonoil, cocoa, menthol, orange oil, peppermint oil and vanillin);

humectants (examples include but are not limited to glycerol, propyleneglycol and sorbitol);

levigating agents (examples include but are not limited to mineral oiland glycerin);

oils (examples include but are not limited to arachis oil, mineral oil,olive oil, peanut oil, sesame oil and vegetable oil);

ointment bases (examples include but are not limited to lanolin,hydrophilic ointment, polyethylene glycol ointment, petrolatum,hydrophilic petrolatum, white ointment, yellow ointment, and rose waterointment);

penetration enhancers (transdermal delivery) (examples include but arenot limited to monohydroxy or polyhydroxy alcohols, mono-or polyvalentalcohols, saturated or unsaturated fatty alcohols, saturated orunsaturated fatty esters, saturated or unsaturated dicarboxylic acids,essential oils, phosphatidyl derivatives, cephalin, terpenes, amides,ethers, ketones and ureas)

plasticizers (examples include but are not limited to diethyl phthalateand glycerol);

solvents (examples include but are not limited to ethanol, corn oil,cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanutoil, purified water, water for injection, sterile water for injectionand sterile water for irrigation);

stiffening agents (examples include but are not limited to cetylalcohol, cetyl esters wax, microcrystalline wax, paraffin, stearylalcohol, white wax and yellow wax);

suppository bases (examples include but are not limited to cocoa butterand polyethylene glycols (mixtures));

surfactants (examples include but are not limited to benzalkoniumchloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium laurylsulfate and sorbitan mono-palmitate);

suspending agents (examples include but are not limited to agar,bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,kaolin, methylcellulose, tragacanth and veegum);

sweetening agents (examples include but are not limited to aspartame,dextrose, glycerol, mannitol, propylene glycol, saccharin sodium,sorbitol and sucrose);

tablet anti-adherents (examples include but are not limited to magnesiumstearate and talc);

tablet binders (examples include but are not limited to acacia, alginicacid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose,gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone, and pregelatinized starch);

tablet and capsule diluents (examples include but are not limited todibasic calcium phosphate, kaolin, lactose, mannitol, microcrystallinecellulose, powdered cellulose, precipitated calcium carbonate, sodiumcarbonate, sodium phosphate, sorbitol and starch);

tablet coating agents (examples include but are not limited to liquidglucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetatephthalate and shellac);

tablet direct compression excipients (examples include but are notlimited to dibasic calcium phosphate);

tablet disintegrants (examples include but are not limited to alginicacid, carboxymethylcellulose calcium, microcrystalline cellulose,polacrillin potassium, cross-linked polyvinylpyrrolidone, sodiumalginate, sodium starch glycollate and starch);

tablet glidants (examples include but are not limited to colloidalsilica, corn starch and talc);

tablet lubricants (examples include but are not limited to calciumstearate, magnesium stearate, mineral oil, stearic acid and zincstearate);

tablet/capsule opaquants (examples include but are not limited totitanium dioxide);

tablet polishing agents (examples include but are not limited to carnubawax and white wax);

thickening agents (examples include but are not limited to beeswax,cetyl alcohol and paraffin);

tonicity agents (examples include but are not limited to dextrose andsodium chloride);

viscosity increasing agents (examples include but are not limited toalginic acid, bentonite, carbomers, carboxymethylcellulose sodium,methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth);and

wetting agents (examples include but are not limited toheptadecaethylene oxycetanol, lecithins, sorbitol monooleate,polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

Pharmaceutical compositions according to the present invention can beillustrated as follows:

Sterile IV Solution: A 5 mg/mL solution of the desired compound of thisinvention can be made using sterile, injectable water, and the pH isadjusted if necessary. The solution is diluted for administration to 1-2mg/mL with sterile 5% dextrose and is administered as an IV infusionover about 60 minutes.

Lyophilized powder for IV administration: A sterile preparation can beprepared with (i) 100-1000 mg of the desired compound of this inventionas a lypholized powder, (ii) 32-327 mg/mL sodium citrate, and (iii)300-3000 mg Dextran 40. The formulation is reconstituted with sterile,injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL,which is further diluted with saline or dextrose 5% to 0.2-0.4 mg/mL,and is administered either IV bolus or by IV infusion over 15-60minutes.

Intramuscular suspension: The following solution or suspension can beprepared, for intramuscular injection:

50 mg/mL of the desired, water-insoluble compound of this invention

5 mg/mL sodium carboxymethylcellulose

4 mg/mL TWEEN 80

9 mg/mL sodium chloride

9 mg/mL benzyl alcohol

Hard Shell Capsules: A large number of unit capsules are prepared byfilling standard two-piece hard galantine capsules each with 100 mg ofpowdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6mg of magnesium stearate.

Soft Gelatin Capsules: A mixture of active ingredient in a digestibleoil such as soybean oil, cottonseed oil or olive oil is prepared andinjected by means of a positive displacement pump into molten gelatin toform soft gelatin capsules containing 100 mg of the active ingredient.The capsules are washed and dried. The active ingredient can bedissolved in a mixture of polyethylene glycol, glycerin and sorbitol toprepare a water miscible medicine mix.

Tablets: A large number of tablets are prepared by conventionalprocedures so that the dosage unit is 100 mg of active ingredient, 0.2mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg ofmicrocrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose.Appropriate aqueous and non-aqueous coatings may be applied to increasepalatability, improve elegance and stability or delay absorption.

Immediate Release Tablets/Capsules: These are solid oral dosage formsmade by conventional and novel processes. These units are taken orallywithout water for immediate dissolution and delivery of the medication.The active ingredient is mixed in a liquid containing ingredient such assugar, gelatin, pectin and sweeteners. These liquids are solidified intosolid tablets or caplets by freeze drying and solid state extractiontechniques. The drug compounds may be compressed with viscoelastic andthermoelastic sugars and polymers or effervescent components to produceporous matrices intended for immediate release, without the need ofwater.

Method of Treating Multiple Myeloma

The present invention relates to a method for using the compounds of thepresent invention and compositions thereof, to treat mammalian multiplemyeloma. Compounds can be utilized to inhibit, block, reduce, decrease,etc., cell proliferation and/or cell division, and/or produce apoptosis,in the treatment or prophylaxis of multiple myeloma. This methodcomprises administering to a mammal in need thereof, including a human,an amount of a compound of this invention, or a pharmaceuticallyacceptable salt, isomer, polymorph, metabolite, hydrate, solvate orester thereof; etc. which is effective for the treatment or prophylaxisof multiple myeloma, which, as mentioned supra, is also known asmyeloma, plasma cell myeloma, or as Kahler's disease (after OttoKahler), which is a type of cancer of plasma cells in bone marrow thatproduce antibodies.

This disorder has been well characterized in humans, but also existswith a similar etiology in other mammals, and can be treated byadministering pharmaceutical compositions of the present invention.

The term “treating” or “treatment” as stated throughout this document isused conventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving thecondition of, etc., of a disease or disorder, such as a carcinoma.

Dose and Administration

Based upon standard laboratory techniques known to evaluate compoundsuseful for the treatment or prophylaxis of multiple myeloma, by standardtoxicity tests and by standard pharmacological assays for thedetermination of treatment of the conditions identified above inmammals, and by comparison of these results with the results of knownmedicaments that are used to treat these conditions, the effectivedosage of the compounds of this invention can readily be determined fortreatment of the indication. The amount of the active ingredient to beadministered in the treatment of the condition can vary widely accordingto such considerations as the particular compound and dosage unitemployed, the mode of administration, the period of treatment, the ageand sex of the patient treated, and the nature and extent of thecondition treated.

The total amount of the active ingredient to be administered willgenerally range from about 0.001 mg/kg to about 200 mg/kg body weightper day, and preferably from about 0.01 mg/kg to about 20 mg/kg bodyweight per day. Clinically useful dosing schedules will range from oneto three times a day dosing to once every four weeks dosing. Inaddition, “drug holidays” in which a patient is not dosed with a drugfor a certain period of time, may be beneficial to the overall balancebetween pharmacological effect and tolerability. A unit dosage maycontain from about 0.5 mg to about 1,500 mg of active ingredient, andcan be administered one or more times per day or less than once a day.The average daily dosage for administration by injection, includingintravenous, intramuscular, subcutaneous and parenteral injections, anduse of infusion techniques will preferably be from 0.01 to 200 mg/kg oftotal body weight. The average daily rectal dosage regimen willpreferably be from 0.01 to 200 mg/kg of total body weight. The averagedaily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kgof total body weight. The average daily topical dosage regimen willpreferably be from 0.1 to 200 mg administered between one to four timesdaily. The transdermal concentration will preferably be that required tomaintain a daily dose of from 0.01 to 200 mg/kg. The average dailyinhalation dosage regimen will preferably be from 0.01 to 100 mg/kg oftotal body weight.

Of course the specific initial and continuing dosage regimen for eachpatient will vary according to the nature and severity of the conditionas determined by the attending diagnostician, the activity of thespecific compound employed, the age and general condition of thepatient, time of administration, route of administration, rate ofexcretion of the drug, drug combinations, and the like. The desired modeof treatment and number of doses of a compound of the present inventionor a pharmaceutically acceptable salt or ester or composition thereofcan be ascertained by those skilled in the art using conventionaltreatment tests.

Combination Therapies

The compounds of this invention can be administered as the solepharmaceutical agent or in combination with one or more otherpharmaceutical agents where the combination causes no unacceptableadverse effects. For example, the compounds of this invention can becombined with known anti-angiogenesis, anti-hyper-proliferative,antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic,anti-hypercholsterolennia, anti-dyslipidemia, anti-diabetic or antiviralagents, and the like, as well as with admixtures and combinationsthereof.

EXAMPLES

The invention is demonstrated in the following examples which are notmeant to limit the invention in any way:

Example 1

In accordance with the invention, the compounds were assessed in acell-based assay that measures the capacity of the compounds to inhibittumor cell proliferation following a 72-hour drug exposure. Cellviability is determined using CellTiter-Glo® Luminescent Cell ViabilityAssay (Promega). Cells were plated at 2000-5000 cells/well (depending onthe cell lines) in 100 μL growth medium on 96-well microtiterplate. Foreach cell line assayed, cells were plated onto a separate plate fordetermination of Luminescence at t=0 hour and t=72 hour time points.Following overnight incubation at 37° C., Luminescence values for thet=0 samples were determined. Dose plates for the t=72 hour time pointswere treated with compounds diluted into growth medium. Cells were thenincubated for 72 hours at 37° C. Luminescence values for the t=72 hoursamples were determined. For data analysis, briefly, t=0 values weresubtracted from those determined for the t=72 hour time points, for boththe treated and untreated samples. Percent differences in fluorescencebetween drug-treated and control values were used to determine thepercent inhibition of growth.

IC₅₀ values for the compound2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide,of structure:

hereinafter referred to as compound A, in this functional assay werepresented in Table I. Compound A strongly inhibits the proliferation of9 multiple myeloma tested with IC50s ranging from 3-100 nM. These datasuggested that compound A has equal or even more potentantiproliferative activity in comparison to the current standards ofcare drugs for multiple myeloma, such as Bortezomib,Thalidomide/lenalidomide, Dexamethasone and Melphalan.

TABLE 1 IC50s of compound A in proliferation assays with multiplemyeloma cell lines KMS-12-BM KMS-12-PE L363 LP-1 Molm13 Molp2 Molp8 RPMI8226 OPM2 Compound A 3.7E−09 6.7E−08 8.1E−09 3.7E−09 6.9E−08 1.2E−082.3E−08 4.80E−08 9.20E−08

As neoangiogenesis has been suggested playing important role instimulating proliferation, survival, and drug resistance of multiplemyeloma through paracrine and cell adhesion-mediated interactionssimilar to those between MM cells and BMSCs, the effect of testcompounds on endothelial cell proliferation may be evaluated.

Control Substances

Rapamicin (obtained from Sigma, St Louis, Mo., USA) is used as areference inhibitor.

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1. A method for the treatment of multiple myeloma comprisingadministering to mammal in need thereof an effective amount of acompound of general formula:

or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof, in which: R¹ represents—(CH₂)_(n)—(CHR⁴)—(CH₂)_(m)—N(R⁵)(R^(5′)); R² represents a heteroaryloptionally substituted with 1, 2 or 3 R⁶ groups; R³ represents alkyl orcycloalkyl; R⁴ represents hydrogen, hydroxy or alkoxy; R⁵ and R^(5′) maybe the same or different and are independently, hydrogen, alkyl,cycloalkylalklyl, or alkoxyalkyl or R⁵ and R^(5′) may be taken togetherwith the nitrogen atom to which they are bound to form a 3-7 memberednitrogen containing heterocyclic ring optionally containing at least oneadditional heteroatom selected from oxygen, nitrogen or sulfur and whichmay be optionally substituted with 1 or more R^(6′) groups, or R⁴ and R⁵may be taken together with the atoms to which they are bound to form a5-6 membered nitrogen containing heterocyclic ring optionally containing1 or more nitrogen, oxygen or sulfur atoms and which may be optionallysubstituted with 1 or more R⁶′ groups; each occurrence of R⁶ may be thesame or different and is independently halogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalklyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclic ring, heterocyclylalkyl, alkyl-OR⁷,alkyl-SR⁷, alkyl-N(R⁷)(R^(7′)), alkyl-COR⁷, —CN, —COOR⁷,—CON(R⁷)(R^(7′)), —OR′, —SR′, —N(R⁷)(R^(7′)), or —NR⁷COR⁷ each of whichmay be optionally substituted with 1 or more R⁸ groups; each occurrenceof R^(6′) may be the same or different and is independently alkyl,cycloalkylalklyl, or alkyl-OR⁷; each occurrence of R⁷ and R^(7′) may bethe same or different and is independently hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalklyl, cycloalkenyl, aryl, arylalkyl,heteroaryl, heterocyclic ring, heterocyclylalkyl, or heteroarylalkyl;each occurrence of R⁸ is independently nitro, hydroxy, cyano, formyl,acetyl, halogen, amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,cycloalkylalklyl, cycloalkenyl, aryl, arylalkyl, heteroaryl,heterocyclic ring, heterocyclylalkyl, or heteroarylalkyl; n is aninteger from 1-4 and m is an integer from 0-4 with the proviso that whenwhen R⁴ and R⁵ are taken together with the atoms to which they are boundto form a 3-7 membered nitrogen containing ring, n+m≦4.
 2. The methodaccording to claim 1, wherein in said compound of formula (I), R² is anitrogen containing heteroaryl optionally substituted with 1, 2 or 3 R⁶groups.
 3. The method according to claim 1, wherein in said compound offormula (I), R⁵ and R^(5′) are independently alkyl.
 4. The methodaccording to claim 1, wherein in said compound of formula (I), R⁵ andR^(5′) are taken together with the nitrogen atom to which they are boundto form a 5-6 membered nitrogen containing heterocyclic ring containingat least one additional heteroatom selected from oxygen, nitrogen orsulfur and which may be optionally substituted with 1 or more R^(6′)groups.
 5. The method according to claim 1, wherein in said compound offormula (I), R⁴ is hydroxy.
 6. The method according to claim 1, whereinin said compound of formula (I), R⁴ and R⁵ are taken together with theatoms to which they are bound to form a 5-6 membered nitrogen containingheterocyclic ring optionally containing 1 or more nitrogen, oxygen orsulfur atoms and which may be optionally substituted with 1 or moreR^(6′) groups.
 7. The method according to claim 1, wherein in saidcompound of formula (I), R³ is methyl.
 8. The method according to claim1, wherein in said compound of formula (I), R² is pyridine, pyridazine,pyrimidine, pyrazine, pyrole, oxazole, thiazole, furan or thiophene,optionally substituted with 1, 2 or 3 R⁶ groups.
 9. The method accordingto claim 1, wherein in said compound of formula (I), R² is pyridine,pyridazine, pyrimidine, pyrazine, pyrole, oxazole or thiazole,optionally substituted with 1, 2 or 3 R⁶ groups.
 10. The methodaccording to claim 1, wherein said compound is of the formula:


11. The method according to claim 10, wherein in said compound, R² ispyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole, thiazole,furan or thiophene, optionally substituted with 1, 2 or 3 R⁶ groups. 12.The method according to claim 11, wherein in said compound, R² ispyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole or thiazole,optionally substituted with 1, 2 or 3 R⁶ groups.
 13. The methodaccording to claim 1, wherein said compound of formula (I) has theformula:


14. The method according to claim 13, wherein in said compound, R² ispyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole, thiazole,furan or thiophene, optionally substituted with 1, 2 or 3 R⁶ groups. 15.The method according to claim 14, wherein in said compound, R² ispyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole or thiazole,optionally substituted with 1, 2 or 3 R⁶ groups.
 16. The methodaccording to claim 1, wherein said compound of formula (I) is of theformula:


17. The method according to claim 16, wherein in said compound, R² ispyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole, thiazole,furan or thiophene, optionally substituted with 1, 2 or 3 R⁶ groups. 18.The method according to claim 17, wherein in said compound, R² ispyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole or thiazole,optionally substituted with 1, 2 or 3 R⁶ groups.
 19. The methodaccording to claim 1, wherein said compound has the formula:


20. The method according to claim 19, wherein in said compound, R² ispyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole, thiazole,furan or thiophene, optionally substituted with 1, 2 or 3 R⁶ groups. 21.The method according to claim 20, wherein in said compound, R² ispyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole or thiazole,optionally substituted with 1, 2 or 3 R⁶ groups.
 22. The method of claim19, wherein in said compound, R^(5′) is alkyl.
 23. The method accordingto claim 1, wherein said compound is of the formula:


24. The method according to claim 23, wherein in said compound, R² ispyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole, thiazole,furan or thiophene, optionally substituted with 1, 2 or 3 R⁶ groups. 25.The method according to claim 24, wherein in said compound, R² ispyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole or thiazole,optionally substituted with 1, 2 or 3 R⁶ groups.
 26. The methodaccording to claim 23, wherein in said compound, R^(5′) is alkyl. 27.The method according to claim 1, wherein said compound is, namely:N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-2,4-dimethyl-1,3-thiazole-5-carboxamide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1,3-thiazole-5-carboxamide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]isonicotinamide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-4-methyl-1,3-thiazole-5-carboxamide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-4-propylpyrimidine-5-carboxamide;N-{8-[2-(4-ethylmorpholin-2-yl)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide;N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide1-oxide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-(2-pyrrolidin-1-ylethyl)nicotinamide;6-(cyclopentylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[8-(2-hydroxy-3-morpholin-4-ylpropoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-{7-methoxy-8-[3-(3-methylmorpholin-4-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-(8-{2-[4-(cyclobutylmethyl)morpholin-2-yl]ethoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-(7-methoxy-8-{2-[4-(2-methoxyethyl)morpholin-2-yl]ethoxy}-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-{8-[(4-ethylmorpholin-2-yl)methoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-(7-methoxy-8-{[4-(2-methoxyethyl)morpholin-2-yl]methoxy}-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-{7-methoxy-8-[(4-methylmorpholin-2-yl)methoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-4-carboxamide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-4-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-methyl-1H-imidazole-4-carboxamide;rel-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide;rel-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-6-methylnicotinamide;rel-6-acetamido-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-methyl-1H-imidazole-5-carboxamide;6-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-methylnicotinamide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-4-methylpyrimidine-5-carboxamide;6-amino-5-bromo-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1,3-oxazole-5-carboxamide;N-[7-methoxy-8-(morpholin-2-ylmethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;2-{[2-(dimethylamino)ethyl]amino}-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide;2-amino-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}-1,3-thiazole-5-carboxamide;rel-2-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide;rel-6-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;2-[(2-hydroxyethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-[(3-methoxypropyl)amino]pyrimidine-5-carboxamide;2-amino-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-[(3-morpholin-4-ylpropyl)amino]pyrimidine-5-carboxamide;2-[(2-methoxyethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;2-{[2-(dimethylamino)ethyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;6-amino-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-pyrrolidin-1-ylpyrimidine-5-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-morpholin-4-ylpyrimidine-5-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-piperazin-1-ylnicotinamidehydrochloride;6-[(3S)-3-aminopyrrolidin-1-yl]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamidehydrochloride hydrate;6-[(3R)-3-aminopyrrolidin-1-yl]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamidehydrochloride;6-[(4-fluorobenzyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;6-[(2-furylmethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;6-[(2-methoxyethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-(1H-pyrrol-1-yl)nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-morpholin-4-ylnicotinamide;N-{7-methoxy-8-[3-(methylamino)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;6-[(2,2-dimethylpropanoyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;6-[(cyclopropylcarbonyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamideN-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-(2,2,2-trifluoroethoxy)nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-(trifluoromethyl)nicotinamide;6-(isobutyrylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-{7-methoxy-8-[3-(4-methylpiperazin-1-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-{[(methylamino)carbonyl]amino}-1,3-thiazole-4-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-{[(methylamino)carbonyl]amino}nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-(methylamino)-1,3-thiazole-4-carboxamide;N-[7-methoxy-8-(2-morpholin-4-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}-2,4-dimethyl-1,3-thiazole-5-carboxamide;N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}-6-methylnicotinamide;6-{[(isopropylamino)carbonyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-pyrrolidin-1-ylnicotinamide;6-(dimethylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(3-piperidin-1-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(2-pyrrolidin-1-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(2-piperidin-1-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;6-{[(ethylamino)carbonyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;6-fluoro-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1,3-oxazole-4-carboxamide;2-(ethylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1,3-thiazole-4-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrazine-2-carboxamide;N-[8-(2-aminoethoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;6-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]isonicotinamide;N-{8-[3-(diethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-{8-[2-(diisopropylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-{8-[2-(diethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-(methylamino)pyrimidine-5-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-(methylthio)pyrimidine-5-carboxamide;N-[8-(3-aminopropoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamidetrifluoroacetate;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]thiophene-2-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2,4-dimethyl-1,3-thiazole-5-carboxamide;2-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-3-furamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]thiophene-3-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2-methyl-1,3-thiazole-4-carboxamide;6-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;5-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-methylnicotinamide;6-(acetylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof.
 28. The method according to claim 1, wherein said compound is,namely:N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-6-methylnicotinamide;5-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-2,4-dimethyl-1,3-thiazole-5-carboxamide;N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;6-{[(isopropylamino)carbonyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}-2,4-dimethyl-1,3-thiazole-5-carboxamide;N-[7-methoxy-8-(2-morpholin-4-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;rel-6-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;rel-2-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide;2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide;N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;or a physiologically acceptable salt, solvate, hydrate or stereoisomerthereof.